Abstract

Innate immune signaling activation and DNA damage are pathological hallmarks of aging that may herald multiple adult-onset neurodegenerative diseases. Here, we report that production of cytoplasmic double-stranded RNA (cdsRNA) in murine olfactory neurons from a regulated, disarticulated transgene induces type I interferon (IFN-I) signaling and neuronal death in both a cell autonomous and non-autonomous manner. CdsRNA is a pathogen associated molecular pattern that induces IFN-I in other cell types. Transfection of a dsRNA mimetic into cultured human neurons also induces IFN-I signaling and cell death. Direct relevance to human disease is found in neurons of ALS-FTD patients carrying C9ORF72 intronic hexanucleotide expansions; cdsRNA isolated from these tissues is comprised of repeat sequences. Together, these findings implicate cdsRNA generated from genomic sequences in neurons as a trigger for sterile, viral-mimetic IFN-I induction and propagated death within in a neural circuit.

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